The parathyroid gland is the major endocrine organ which regulates extracellular calcium by secreting parathyroid hormone (PTH). Extracellular calcium is not only vital to fundamental cellular functions, but also plays pivotal roles in the metabolism of skeletal tissues and teeth. The feed-back mechanism of calcium regulation by PTH involves sensing of extracellular calcium concentration by parathyroid cells and mobilization of calcium by PTH at peripheral tissues. Among the peripheral tissues responsive to PTH, cells in an osteoblast lineage appear to be most important in inducing bone resorption by osteoclast and in regulating extracellular calcium concentration. The main purpose of this program is to study (1) how parathyroid cells sense extracellular calcium concentration, (2) how this signal regulates parathyroid cell functions, including cell growth and hormone secretion, and (3) how functions of osteoblasts and osteoclasts are regulated by PTH, cytokines and growth factors. We have established a unique parathyroid cell line which retains its physiological functions in culture. Parathyroid cell growth regulation by extracellular calcium has been demonstrated by us to be highly dependent on an autocrine system involving acidic fibroblast growth factor (aFGF) and its cell surface receptor (aFGF-R). The mechanism of PTH secretory regulation by calcium is currently not well understood. The calcium- sensing receptor, a G-protein coupled receptor, on the parathyroid cell surface appears to play a major role, but there is evidence that other factors modulate the regulation mediated by the calcium-sensing receptor. We have previously reported that endothelin 1 (ET-1) and its receptor (ETA receptor) form an autocrine loop in parathyroid cells, and that this autocrine loop is regulated by extracellular calcium concentration. In another aspect of mineral metabolism, to understand the regulatory mechanisms of osteoblasts by external stimuli, it is important to know intracellular signal transduction pathways unique to them. The topics of current interest are to study effects of extracellular calcium on the expression and post-translational modification of aFGF and aFGF-R by parathyroid cells, to understand the regulatory mechanisms of PTH secretion by the ET-1/ETA receptor autocrine loop, and to elucidate the signal transduction pathways unique to the cells in an osteoblast lineage.